Chromogranin A (CHGA), a 48 kDa acidic secretory protein, is co-stored with neurotransmitters (catecholamines, ATP, and neuropetide Y [NPY]) in vesicles called chromaffin granules and co-released in response to nicotinic-cholinergic stimulation. CHGA is a proprotein giving rise to biologically active peptides including a catecholamine release inhibitory peptide (bovine CHGA344.364 and human CHGA352.372) that we discovered and named catestatin. Since genetically modified mice are becoming increasingly important in studies designed to understand basic mechanisms of cardiovascular function, we have generated systemic and conditional Chga knockout (Chga-/-) mice. The systemic Chga-/- mice displayed the following phenotypes: (i) Depletion of chromaffin granules accompanied by higher systolic and diastolic blood pressure (BP), (ii) "Non-dipping" BP (no diurnal variation), (iii) Increment of left ventricular dimension, (iv) Decrements of adrenal catecholamine, NPY and ATP levels, (v) Increments of plasma catecholamine and NPY levels, and (vi) Exaggerated BP response to treadmill stress. We have already generated bacterial artificial chromosome (BAG) transgenic mice containing the human CHGA gene (CHGA+/+) into the germline of Chga-/- mice (CHGA+/+;Chga-/-) to "rescue" Chga knockout phenotypes. The present proposal develops 3 specific aims: Aim I. Explore the mechanism of development of high BP (SBP and DBP) and "non-dipping" BP phenotypes in Chga-/- mice, including the role of cotransmitters. Aim II. "Rescue" the BP and "nondipping" BP phenotypes observed in Chga-/- mice by introduction of a BAG containing the human CHGA gene (CHGA+/+) into the germline of Chga-/- mice (CHGA+/+\Chga-/-). Aim III. Establish the role of a naturally occurring human catestatin variant in mice (expressing a BAC-catestatin variant transgene) in counteracting sympathoadrenal stress BP responses. These studies, utilizing unique knockout, transgenic, and human variants of catestatin, are likely to establish the role of CHGA fragment catestatin and catecholamine co-transmitters in the development of complex phenotypes such as hypertension, and the influence of naturally occurring catestatin variants in counteracting BP responses to sympathoadrenal stressors.